Metastatic cancers with uncertain primary sites account for a significant portion of new cases. Among them, 3-9% are eventually assigned to cancer of unknown primary (CUP) site after a comprehensive diagnostic workup. Accurate identification of the primary site is the starting point for cancer diagnosis worldwide, and it is critical to guide the subsequent treatments of metastatic cancers. Here we presented a new DNA methylation sequencing-based method to predict the tissues of origin for metastatic cancers, including CUP.